Regulation of neurotrophic signaling molecules in motor neurons, primary sensory neurons and target tissues in senescence

Abstract

A hallmark of senescence is sensorimotor impairment, characterized by gait disturbance, deficits in postural control, and muscle weakness. The object of this thesis work was to elucidate some of the molecular basis underlying these disturbances, mainly referring to the occurrence of characteristic changes in gene-expression pattern, especially, alterations in trophic signaling associated with the phenotypic changes seen in motoneurons as well as primary sensory neurons and target muscles during aging.

Based on our previous findings of trk downregulation in aging DRG and spinal motoneurons that may reflect a failure of targets to supply neurotrophic factors, the expression of neurotrophins in target tissues and peripheral nerves of aged rats was examined by use of RT-PCR. In target muscles, decreased levels of NGF, BDNF, NT3, NT4 mRNAs were observed, and notably, the decrease covaried with the extent of behavioural sensorimotor disturbances among the aged individuals. In contrast, the peripheral nerve of aged rats showed a reciprocal regulation of NGF, BDNF and NT4 mRNAs. These aging-related changes provide evidence of an attenuated neurotrophin-trk-signaling in senescence, possibly relating to a breakdown in the neuron-target interaction, which may explain some of the phenotypic changes of senescent neurons.

In contrast, a dramatic upregulation of GDNF mRNA was detected in target muscles and to a lesser extent also in peripheral nerve during aging. A parallel increase of the preferred receptors, GFRalpha1 and c-Ret, in primary sensory neurons and motoneurons strongly indicates an enhanced GDNF signaling in senescence. The phenomenon of an increased GDNF signaling between the target muscles and motoneurons may serve as a compensatory mechanism in the context of decreased neurotrophin-trk signaling in aged motoneurons, promoting axon regeneration, sprouting, and muscle fibre re-innervation. Since GDNF has been suggested to act primarily on unmyelinated PSN, an increased GDNF-GFRalpha1/Ret signaling and a decreased neurotrophin siganling mutually may clarify many of the senescent phenotypic changes of primary sensory neurons, and may explain why unmyelinated primary afferents are better preserved during aging.

A slight upregulation of FGF-2/FGFR1 signaling was established, whereas the gpl30 signaling components (CNTF, IL-6, LIF, CNTFRalpha, LIFR, IL-6R or gpl30) were maintained at young adult level in the aged spinal cord, indicating that FGF/FGFR1 signaling may be involved in the phenotypic changes of aged motoneurons but the gp 130 cytokines continue to support motoneurons at about the same level throughout life. In the target muscles, there were a marked downregulation of IL-6 and FGF-2 mRNAs and an upregulation of FGFR1, CNTFRalpha as well as gpl30. It is suggested that these regulations reflect the repair situation in senescent muscles.

The changes in cytokine expressions showed an increased IFN-gamma signaling and in parallel an increase of other cytokines as IL- I beta, IL-6 and TGF-beta1 in senescent spinal cord, which may provide evidence of the involvement of inflammation during aging, marked by gliosis associated with axon dystrophy, myelin aberrations and synaptic disconnection.